Palladium‐Catalyzed 8‐Aminoquinoline‐Aided sp²δ‐C−H Intramolecular Amidation/Annulation: A Route to Tricyclic Quinolones

Abstract

Systematic investigations of a Pd(II)-catalyzed, 8aminoquinoline directing group (DG)-aided sp 2 δ-CÀ H amidation (CÀ N bond formation) of different biaryl carboxamides are reported. Various biaryl carboxamides with suitably positioned sp 2 δ-CÀ H bond with respect to the DG were assembled via β-CÀ H arylation and then they were subjected to Pd(II)-catalyzed sp 2 δ-CÀ H intramolecular amidation/annulation reactions. While the intramolecular amidation of the sp 2 δ-CÀ H bond of some carboxamides was not fruitful, several biaryl carboxamides underwent intramolecular amidation of their sp 2 δ-CÀ H bonds to afford various tricyclic quinolone motifs such as, phenanthridin-6(5H)-ones and thieno-/furo-/pyrrolo-[2,3-c]quinolin-4(5H)-ones. The assembly of the required biaryl carboxamides possessing the sp 2 δ-CÀ H bond via the β-CÀ H arylation and the successive intramolecular amidation (CÀ N bond formation) of the resulting biaryl carboxamides were also performed in one-pot reaction conditions to afford tricyclic quinolones. . Directing group-aided site-selective CÀ H activation. Scheme 2. Intramolecular amidation of the remote CÀ H bonds. . Assembling of 12 a-j suitably positioned with the sp 2 δ-CÀ H bond via the AQ-aided β-CÀ H arylation. Scheme 9. The Pd[II]-catalyzed, AQ-aided intramolecular amidation of 12 a-j.

A Guide to Directing Group Removal: 8‐Aminoquinoline

“…Unlike substrates with cycloalkyl substituents (all previous examples), lactams in which the aminoquinoline amide is incorporated into the ring ( 87 – 89 , Scheme 14) are a special case that require cleavage of the N−Q bond (as opposed to the (O)C−N bond discussed so far). These molecules are particularly resistant to AQ cleavage and all attempts to remove the directing group from compounds 87 – 89 were unsuccessful [69, 70] . Some success has been reported by changing to the more labile MQ (Section 2.2) [71] or N ‐amino‐7‐azaindole (Section 3.2) [72] directing groups which could be removed from 90 and 91 to give the desired lactam in 66 % yield and 80 % yield, respectively, however this strategy is not always successful.…”

Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp2/sp3γ‐C−H and sp2δ‐C−H Functionalization of Carboxamides

“…Treatment of thiophene/furan‐based biaryl carboxamides 15 a , b , d , e and 16 a – d with PhI(OAc) 2 in the presence of Pd(OAc) 2 (10 mol%) in toluene at 110 °C successfully afforded the expected thieno[2,3‐ c ]quinolin‐4(5 H )‐one and furano[2,3‐ c ]quinolin‐4(5 H )‐one motifs 19 a – d and 20 a – d in 37–81% yields (Scheme 8). It was noted that the performance of the pyridine‐ N ‐oxide DG in the δ‐ C(sp 2 )−H amidation of substrates 15 / 16 is comparable to the earlier reported process involving the 8‐aminoquinoline DG [8b] . Nevertheless, functionalized thiophenes/furans and benzothiophenes/benzofurans are an important class of compounds in organic synthesis, materials, and medicinal chemistry [16] .…”

“…Having investigated the γ‐ C(sp 2 )−H arylation of arylacetamides and methyl γ‐ C(sp 3 )−H bond of 3‐methylheteroaryl‐2‐carboxamides using the pyridine‐ N ‐oxide DG, we then wished to attempt the δ‐ C(sp 2 )−H functionalization in carboxamides. Taking an impetus from our earlier work, [8b] involving the Pd(II)‐catalyzed, 8‐aminoquinoline DG‐aided aided δ ‐C(sp 2 )−H amidation (C−N bond formation) of heteroaryl‐based biaryl carboxamides, we intended to investigate the scope of the pyridine‐ N ‐oxide DG in the δ ‐C(sp 2 )−H amidation (C−N bond formation) of heteroaryl‐based biaryl carboxamides.…”

“…Having assembled the required examples of heteroaryl‐based biaryl carboxamides 15 / 16 with suitably positioned δ ‐C(sp 2 )−H bond with respect to the pyridine‐ N ‐oxide DG, we then subjected the substrates 15 / 16 to the Pd(II)‐catalyzed δ ‐C(sp 2 )−H amidation reaction conditions [8b] (Scheme 8). These reactions are expected to afford the corresponding phenanthridin‐6(5 H )‐ones (tricyclic quinolones) via the pyridine‐ N ‐oxide DG‐aided intramolecular δ ‐C(sp 2 )−H amidation (via C−N bond formation).…”

Diastereoselective palladium-catalyzed functionalization of prochiral C(sp3)–H bonds of aliphatic and alicyclic compounds

“…The DG-aided functionalization of the β-C–H bonds of carboxylic acids and γ-C–H bonds of amines are commonly explored processes. 1–3,5–9,13,14 These processes proceed via the highly favored five-membered metallacycle intermediates 1c and 1f , respectively. Thus, the γ-, δ- and ε-C–H bonds of carboxylic acids and δ- and ε-C–H bonds of amine substrates are considered to be remote C–H bonds.…”